A Study to Determine the Efficacy and Safety of Luspatercept in Adult Participants and to Evaluate the Safety and Pharmacokinetics in and Adolescent Participants With Alpha (α)-Thalassemia
- Registration Number
- NCT05664737
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
The purpose of the study is to evaluate the efficacy and safety of luspatercept plus best supportive care (BSC) vs placebo plus BSC on anemia in adult participants with α-thalassemia hemoglobin H (HbH) disease and determine the safety and drug levels in adolescent participants.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 249
-
Adult participant≥ 18 years with documented diagnosis of A-Thal HbH disease with Transfusion dependence defined as:.
- TD participant: ≥ 6 RBC units during the 24 weeks prior to randomization.
- NTD participant:< 6 RBC units during the 24 weeks prior to randomization(transfusion due to conditions other than A-Thal will not be considered)and, RBC transfusion-free during at least 8 weeks prior to randomization(unless transfusion was required to treat an acute medical condition other than A-Thal) and, mean baseline Hb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization; hemoglobin values within 21 days post-transfusion will be excluded.
-
Adult participant has Eastern Cooperative Oncology Group (ECOG) 34 score of 0 or 1.
-
Adolescent participant 12 years to < 18 years with documented diagnosis of A-Thal HbH disease with transfusion dependence defined as:.
- TD participant: ≥ 4 RBC events during the 24 weeks prior to enrollment and, no transfusion-free period for > 56 days during the 24 weeks prior to enrollment. Participants must have a history of regular transfusions for at least 2 years.
- NTD participant:< 4 RBC events during the 24 weeks prior to enrollment and RBC transfusion-free during at least 8 weeks prior to enrollment and, mean baseline Hb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to enrollment, hemoglobin values within 21 days post-transfusion will be excluded.
- Participant has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status score ≥ 50 at screening.
Key
- Medical Conditions: Diagnosis of A-ThalTrait, Hb Bart hydrops, ATRx A-Thal, hemoglobin S/β-thalassemia, myelodysplasia subtype anemia, or with HbE homozygous beta gene mutation. Anemia related to nutritional deficiency, anemia of chronic disease, autoimmune hemolytic anemia, or any other hemolytic anemias. Undergone episodes of hemolysis not related to A-Thal within the 8 weeks prior to randomization.
- Participant has deep vein thrombosis (DVT), stroke or other thromboembolic event(s) (except clogged indwelling catheter) requiring medical intervention ≤ 24weeks prior to randomization.
- Participant has uncontrolled hypertension. Controlled hypertension for this protocol is considered: blood pressure value corresponding to ≤Grade 1 according to NCI CTCAE Version 5.0. with or without pharmacological treatment.
- Reproductive Status: Women who are pregnant, plan to get pregnant during the study, or who are breastfeeding.
- Prior/Concomitant: Undergone HSCTs or gene therapy (candidates for HSCT or gene therapy with waiting period of ≥ 12 months are eligible).
- Use of hydroxyurea treatment ≤ 12 weeks prior to enrollment for NTD participants and ≤ 24 weeks for TD participants.
- Participant who has extramedullary hematopoiesis (EMH) complications requiring treatment to control the growth of EMH mass(es) during the screening period.
- Any medical or psychiatric condition (including active infections, recent surgery, sequelae of diseases or interventions, clinically significant laboratory abnormalities or concurrent treatment) that in the opinion of the investigator would put the participant at unacceptable risk of participating in the study or that could affect interpretability of data.
- Other protocol-defined inclusion/exclusion criteria apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Transfusion Dependent (TD): Luspatercept + Best supportive care (BSC) Luspatercept - Adult TD Cohort: Placebo + BSC Placebo - Adult NTD Cohort: Placebo + BSC Placebo - Non-transfusion Dependent (NTD): Luspatercept + BSC Luspatercept -
- Primary Outcome Measures
Name Time Method Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 12 weeks during Week 13-48 compared to 12-week interval immediately prior to date of first dose Up to Week 48 Adult TD Cohort
Dose-limiting toxicities (DLTs) defined as observance of ≥ Grade 3-related hemolytic crises or ≥ Grade 3-related event outside of the known safety profile occurring within the 21 days from their first dose of study therapy Up to Week 3 Adolescent TD and NTD Cohorts
Number of participants with an increase from baseline of ≥ 1.0 grams (g)/decilitre (dL) in mean hemoglobin (Hb) values over the continuous 12-week interval from Week 13 to Week 24 in the absence of RBC transfusion Up to Week 24 Adult NTD Cohort
Number of participants with adverse events (AEs) Up to 8.5 years Adolescent TD and NTD Cohorts
Pharmacokinetics (PK): Serum concentration of Luspatercept Up to Week 102 Adolescent TD and NTD Cohorts
- Secondary Outcome Measures
Name Time Method Number of participants with antidrug antibody (ADA) Up to Week 48 Adolescent TD and NTD Cohorts
Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 24-week interval on treatment compared to 24-week interval immediately prior to date of first dose Up to Week 108 Adult TD Cohort
The longest duration with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units Up to Week 108 Adult TD Cohort
Number of RBC transfusion units from week 1 to week 48 Up to Week 48 Adult and Adolescent TD Cohorts
Change from baseline in hemoglobin in the absence of transfusion at Week 24 Up to Week 24 Adult and Adolescent NTD Cohorts
The longest duration of an increase from baseline of ≥ 1.0 g/dL in mean hemoglobin values starting from Week 13 in the absence of transfusion Up to Week 108 Adult NTD Cohort
Time Duration with an increase from baseline of ≥ 1.0 g/dL in hemoglobin values in the absence of transfusion within 48 weeks Up to Week 48 Adult NTD Cohort
Number of participants with an increase from baseline of ≥1.0 g/dL in mean Hb values over the continuous 12- week interval in the absence of transfusion Up to Week 24 Adult NTD Cohort
≥ 3 Increase from Baseline in Functional Assessment of Cancer Therapy Anemia Fatigue Subscale (FACT-An FS) Score from Baseline to the period from Week 13 to Week 24 Up to Week 24 Adult NTD Cohort
Number of participants with AEs Up to 5 years Adult and Adolescent TD and NTD Cohorts
Number of participants with laboratory abnormalities Up to 5 Years Adult TD and NTD Cohorts
Number of participants with immunogenicity Up to 5 Years Adult TD and NTD Cohorts
Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden during any continuous 24-week interval within 48 weeks compared to the 24-week interval immediately prior to the date of first dose Up to Week 48 Adult TD Cohort
Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden during any continuous 12-week interval compared to the 12-week interval immediately prior to the date of first dose Up to Week 108 Adult TD Cohort
Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden from Week 13 to Week 24 and Week 37 to Week 48 compared to the 12-week interval immediately prior to the date of first dose Up to Week 48 Adult TD Cohort
Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden from Week 1 to Week 24 and Week 25 to Week 48 compared to the 24-week interval immediately prior to the date of first dose Up to Week 48 Adult TD Cohort
Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden from Week 13 to Week 24 and Week 37 to Week 48 compared to the 12-week interval immediately prior to the date of first dose Up to Week 48 Adult TD Cohort
Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden from Week 1 to Week 24 and Week 25 to Week 48 compared to the 24-week interval immediately prior to the date of first dose Up to Week 48 Adult TD Cohort
Change from baseline in total RBC units transfused from Week 1 to Week 24, Week 25 to Week 48, and Week 1 to Week 48 Up to Week 48 Adult TD Cohort
The longest duration of RBC transfusion-free period for participants who achieve transfusion-free period of ≥ 12 weeks Up to Week 108 Adult TD Cohort
The longest duration of reduction in transfusion burden for participants who achieve a response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction) Up to Week 108 Adult TD Cohort
Time from first dose to first day of response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction) Up to Week 108 Adult TD Cohort
Change from baseline in number of transfusion events at Week 48 Up to Week 48 Adult TD Cohort
Number of participants who achieve RBC transfusion-free period of any continuous ≥ 12 weeks during treatment Up to Week 108 Adult and Adolescent TD and NTD Cohorts
Number of participants who achieve RBC transfusion-free period of any continuous ≥ 24 weeks during treatment Up to Week 108 Adult and Adolescent TD and NTD Cohorts
Time to first transfusion Up to Week 108 Adult and Adolescent NTD Cohorts
Number of transfusions Within 48 Weeks Adult NTD Cohort
Number of transfusion visits/units Within 48 Weeks Adult NTD Cohort
Change from baseline in mean hemoglobin values over the continuous 12-week interval from Week 13 to Week 24 and Week 37 to Week 48 in the absence of transfusions Up to Week 48 Adult TD and NTD Cohorts
Number of participants achieving an increase from baseline of ≥1.0g/dL or ≥1.5g/dL in mean Hb values in absence of transfusions from Week 13 to Week 24, Week 37 to Week 48 and during any continuous 12-week window within 24 weeks and 48 weeks Up to Week 48 Adult NTD Cohort
Time from first to last Hb measurement with increase from baseline by ≥ 1.0 g/dL Up to Week 108 Adult NTD Cohorts
Time to the first increase from baseline of ≥ 1.0 g/dL in mean Hb value Up to Week 48 Adolescent NTD Cohort
Number of participants who achieve an increase in mean Hb of >10g/dL values during any continuous 12-week and 24-week interval within 48 weeks in the absence of transfusions Up to Week 48 Adult NTD Cohort
Change from baseline in self-reported health-related quality of life (HRQoL) assessed by physical component summary (PCS) and mental component summary (MCS) of 36-item short-form health survey version2 (SF-36v2) at Week 24 and Week 48 Up to Week 48 Adult TD and NTD Cohorts
Change from baseline in non-transfusion dependent β-thalassemia patient-reported outcome (NTDT-PRO) Tiredness/weakness (T/W) and shortness of breath (SoB) domain scores from Week 13 to Week 24 and from Week 37 to Week 48 Up to Week 48 Adult NTD Cohort
Change from baseline in FACT-An FS Score at Week 24 and Week 48 Up to Week 48 Adult NTD Cohort
Change from baseline in Functional Assessment of Cancer Therapy Anemia Anemia Subscale (FACT-An AS) at Week 24 and Week 48 Up to Week 48 Adult NTD Cohort
Number of participants with at least one hemolytic crisis Up to Week 108 Adult TD and NTD Cohorts
Rate of hemolytic crises Up to Week 108 Adult TD and NTD Cohorts
Time to first hemolytic crisis Up to Week 108 Adult TD and NTD Cohorts
Time to second hemolytic crisis Up to Week 108 Adult TD and NTD Cohorts
Change from baseline in hemolysis markers at Week 24 and Week 48 Up to Week 48 Adult TD and NTD Cohorts:
Change from baseline in the 6-minute walk test (6MWT) distance at Week 24 and Week 48 Up to Week 48 Adult NTD Cohort
Pharmacokinetics (PK): Serum concentration of Luspatercept Up to Week 108 Adult and Adolescent TD and NTD Cohorts
Percent Change from Baseline in Biomarkers for Erythropoiesis at Week 84 Baseline, Week 84 Adult TD and NTD Cohorts
The biomarkers for erythropoiesis to be evaluated include Hb variants including hemoglobin H (HbH), sTfR1, erythropoietin (EPO), growth differentiation factor (GDF11), GDF8, GDF15. The change will be measured as a percentage of change from baseline for all the biomarkers.Percent Change from Baseline in Biomarkers and Parameters for Iron Homeostasis at Week 84 Baseline, Week 84 Adult TD and NTD Cohorts
The biomarkers and parameters for iron homeostasis to be evaluated include hepcidin, erythroferrone (ERFE), serum ferritin, liver iron concentration (LIC), myocardial iron, iron chelation therapy (ICT).
The change will be measured as a percentage of change from baseline for all the biomarkers.Change in mean corpuscular volume (MCV) at Week 48 Baseline, Week 48 Adult TD and NTD Cohorts
Change in mean corpuscular hemoglobin (MCH) at Week 48 Baseline, Week 48 Adult TD and NTD Cohorts
Change in nucleated red blood cells (nRBC) at Week 48 Baseline, Week 48 Adult TD and NTD Cohorts
Change in red blood cells (RBC) at Week 48 Baseline, Week 48 Adult TD and NTD Cohorts
The longest duration with reduction from baseline in the RBC transfusion burden Up to Week 48 Adolescent TD Cohort
The number of participants with ≥ 50% reduction from baseline in RBC transfusion burden during an continuous 12 weeks during Weeks 13-48 Up to Week 48 Adolescent TD Cohort
The number of participants with ≥ 33% reduction from baseline in RBC transfusion burden during an continuous 24 weeks Up to Week 48 Adolescent TD Cohort
Number of participants achieving an increase from baseline of ≥1.0g/dL in mean Hb values in absence of transfusions from Week 13 to Week 24 Up to Week 24 Adolescent NTD Cohort
Cumulative time (in weeks) with an increase from baseline of ≥1.0g/dL in mean Hb values in absence of RBC transfusions within 48 weeks Up to Week 48 Adolescent NTD Cohort
Number of participants who achieve an increase in mean Hb of >10g/dL values during any continuous 12-week interval during week 13 to week 48 in the absence of transfusions Up to Week 48 Adolescent NTD Cohort
The longest duration with an increase from baseline of ≥1.0g/dL in mean Hb values in absence of transfusions Up to Week 48 Adolescent NTD Cohort
Mean change in biomarkers for hemolysis Up to Week 48 Adolescent TD and NTD Cohorts
Biomarkers for hemolysis to be evaluated include total/direct/indirect bilirubin, serum lactate dehydrogenase (sLDH), haptoglobin, reticulocytes and nucleated red blood cells, reticulocyte production index (RPI), and urinary urobilinogenMean change in biomarkers and parameters for iron homeostasis Up to 1 Year Adolescent TD and NTD Cohorts
The biomarkers and parameters for iron homeostasis to be evaluated include serum ferritin, LIC, myocardial iron concentration (MIC), ICT, myocardial T2(TD participants), and extramedullary hematopoiesis (EMH) mass(es) when present (NTD participants)Hematologic assessments Up to Week 48 Adolescent TD and NTD Cohorts
The hematologic assessments to be evaluated are red blood cell count, hemoglobin, hematocrit, reticulocyte count, nucleated red blood cell count, platelet count, mean cell volume, mean cell hemoglobin, mean corpuscular hemoglobin concentration, red blood cell distribution width, red blood cell morphology, and globin precipitatesThe change from baseline in the number of health care resource utilization (HCRU) Up to Week 48 Adolescent TD and NTD Cohorts
Mean change from baseline in Pediatric Quality of Life Inventory (PedsQL) domain scores Up to Week 48 Adolescent TD and NTD Cohorts
Mean change from baseline EQ-5D-5L utility index Up to Week 48 Adolescent TD and NTD Cohorts
Mean change from baseline visual analogue scale (VAS) scores Up to Week 48 Adolescent TD and NTD Cohorts
Trial Locations
- Locations (36)
Local Institution - 0008
🇨🇦Halifax, Nova Scotia, Canada
The First People's Hospital of Foshan
🇨🇳Foshan, Guangdong, China
Local Institution - 0029
🇨🇳Guangzhou, Guangdong, China
Nanfang Hospital of Southern Medical University
🇨🇳Guangzhou, Guangdong, China
Maoming People's Hospital
🇨🇳Maoming Shi, Guangdong, China
Local Institution - 0030
🇨🇳Shenzhen Shi, Guangdong, China
Liuzhou People's Hospital
🇨🇳Liuzhou, Guangxi, China
People's Liberation Army The 923rd Hospital
🇨🇳Nanning Shi, Guangxi, China
Hainan Medical College - First Affiliated Hospital
🇨🇳Haikou, Hainan, China
First People's Hospital of Yunnan Province
🇨🇳Kunming, Yunnan, China
Hainan General Hospital
🇨🇳Haikou, China
The First Affiliated Hospital of Guangxi Medical University
🇨🇳Nanning, China
Local Institution - 0005
🇬🇷Thessaloniki, B, Greece
Local Institution - 0007
🇬🇷Larissa, E, Greece
Local Institution - 0018
🇬🇷Rio, G, Greece
Local Institution - 0006
🇬🇷Athens, Greece
Local Institution - 0009
🇬🇷Goudi, Greece
Queen Mary Hospital
🇭🇰Hong Kong, HK, Hong Kong
Local Institution - 0024
🇭🇰Hong Kong Island, Hong Kong
Local Institution - 0022
🇮🇹Cagliari, CA, Italy
Local Institution - 0026
🇮🇹Genova, GE, Italy
Local Institution - 0020
🇮🇹Orbassano, TO, Italy
Local Institution - 0028
🇮🇹Napoli, Italy
Local Institution - 0019
🇮🇹Napoli, Italy
Local Institution - 0033
🇲🇾Johor Bahru, Malaysia
Local Institution - 0032
🇲🇾Kuala Lumpur, Malaysia
Local Institution - 0035
🇸🇦Al-Ahsa, Saudi Arabia
Local Institution - 0034
🇸🇦Riyadh, Saudi Arabia
Local Institution - 0036
🇸🇬Singapore, Singapore
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳Kaohsiung, KHH, Taiwan
National Taiwan University Hospital
🇨🇳Nan Gang Qu, TPE, Taiwan
China Medical University Hospital
🇨🇳Taichung, TXG, Taiwan
Siriraj Hospital
🇹🇭Bangkok, Thailand
Local Institution - 0031
🇹🇭Mueang Phitsanulok, Thailand
Local Institution - 0027
🇹🇷Altındağ, Turkey
Local Institution - 0021
🇹🇷Topkapı, Turkey